ORGANIC LETTERS
Enantioselective Synthesis of Polycyclic Coumarin Derivatives Catalyzed by an in Situ Formed Primary Amine-Imine Catalyst
2011 Vol. 13, No. 16 4382–4385
Xi Zhu, Aijun Lin, Yan Shi, Jingyu Guo, Chengjian Zhu,* and Yixiang Cheng* School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, P. R. China
[email protected];
[email protected] Received June 27, 2011
ABSTRACT
A facile in situ formed primary amine-imine organocatalyst was developed in the asymmetric Michael addition of substituted 4-hydroxycoumarins to cyclic enones. A series of optically active polycyclic coumarin derivatives were obtained in high yields with excellent enantioselectivities up to 97% ee.
Coumarin derivatives are distributed in a large number of natural products and are commonly used as versatile intermediates in natural product synthesis.1 Modification of this class of compound has been of great interest to chemists due to their various biological activities to antimalarial, anticoagulant, and anti-HIV activities, etc.2 Although most of coumarin derivatives are currently prescribed as the racemate, activity and metabolism are markedly dissimilar for the two enantiomers.3 Therefore, (1) (a) Murray, R. D. H.; Mendez, J.; Brown, R. A. The Natural Coumarins; Wiley: 1982. (b) Kennedy, R. O.; Thornes, R. D. Coumarins: Biology, Applications and Mode of Action; Wiley: 1997. (c) Fylaktakidou, K. C.; Hadjipavlou, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm. Des. 2004, 10, 3813. (2) (a) Melliou, E.; Magiatis, P.; Mitaku, S.; Skaltsounis, A. L.; Chinou, E.; Chinou, I. J. Nat. Prod. 2005, 68, 78. (b) Xie, L.; Takeuchi, Y.; Cosentino, L. M.; McPhail, A. T.; Lee, K. H. J. Med. Chem. 2001, 44, 664. (c) Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S. Tetrahedron: Asymmetry 2001, 12, 707. (d) Ishikawa, T. Heterocycles 2000, 53, 453. (e) Ufer, M. Clin. Pharmacokinet. 2005, 44, 1227. (f) Visser, L. E.; van Schaik, R. H. N.; van Vliet, M.; Trienekens, P. H.; Smet, P. A. G. M. D.; Vulto, A. G.; Hofman, A.; van Duijn, C. M.; Stricker, B. H. C. Clin. Pharmacol. Ther. 2005, 77, 479. (3) (a) O’Reilly, R. A. N. Engl. J. Med. 1976, 295, 354. (b) Wingard, L. B.; O’Reilly, R. A.; Levy, G. Clin. Pharmacol. Ther. 1978, 23, 212. (c) Rang, H. P.; Dale, M. M.; Ritter, J. M.; Gardner, P. Pharmacology, 4th ed.; Churchill Livingstone: Philadelphia, 2001. 10.1021/ol201715h r 2011 American Chemical Society Published on Web 07/19/2011
efficient asymmetric syntheses of coumarins are of longstanding interest.4 Organocatalysis has proven itself a valuable strategy in the preparation of the synthesis of optically active coumarins5 since Jørgensen reported a onestep synthesis of enantiomerically pure warfarin in 2003.6 They presented the first example of an imidazolidine organocatalyst promoted asymmetric Michael reaction of coumarin and R,β-unsaturated ketones.7 Chin and Chen (4) (a) Demir, A. S.; Tanyeli, C.; Gklbeyaz, V.; Akgkn, H. Turk. J. Chem. 1996, 20, 139. (b) Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S. Tetrahedron: Asymmetry 2001, 12, 707. (5) (a) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8, 4851. (b) Halland, N.; Velgarard, T.; Jøgensen, K. A. J. Org. Chem. 2003, 68, 5067. (6) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955. (7) For selected organocatalytic conjugate additions to R,β-unsaturated ketones, see: (a) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4541. (b) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272. (c) Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed. 2004, 43, 3958. (d) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598. (e) Yang, J. Y.; Fonseca, M. T. H.; List, B. J. Am. Chem. Soc. 2005, 127, 15036. (f) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028. (g) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897. (h) Deiana, L.; Zhao, G. L.; Lin, S. Z.; Dziedzic, P.; Zhang, Q.; Leijonmarck, H.; Cordova, A. Adv. Synth. Catal. 2010, 18, 3201. (i) Yanai, H.; Takahashi, A.; Taguchi, T. Chem. Commun. 2010, 46, 8728.
reported the same strategy for the synthesis of pure warfarin catalyzed by a primary amine and diamine, respectively.8 Recently, Xu and Wang independently developed the procedure by chiral squaramides and an amine-thiourea catalyst.9 Good yields and excellent enantioselectivities were obtained with the synthesis strategy above. However, most of the previous research efforts have been limited to a Michael addition reaction with unsubstituted coumarins to modified acyclic enones. Cyclic enones, a special R, β-unsaturated system, still remain as difficult substrates and have been rarely employed as electrophiles in this process. Even for the only example with a 2-cyclohexen-1-one as a cyclic enone donor, the reaction activity was obviously low and a long reaction time (6 days, 78% yield) was required.8a Since the conjugate addition to cyclic enones is an important strategy for the synthesis of active cyclic building blocks, it is therefore of great demand to develop a more effective method to improve the tolerance of cyclic enones and explore more coumarin substrates.
promoted the aldol reaction via an enamine process. Inspired by the finding, we considered that the procedure could be extended to activate the cyclic R,β-unsaturated ketones via an iminium process in the Michael reaction.12 Herein, we describe an asymmetric Michael reaction of 4-hydroxycoumarins and 2-cyclohexen-1-one catalyzed by the in situ formed primary amine-imine catalyst with an (R,R)-diphenylethane backbone to give polycyclic coumarin derivative adducts in high yields and excellent enantioselectivities under mild conditions.
Scheme 1. Application of the in Situ Prepared Primary AmineImine
Figure 1. Structure of diimine precatalysts.
Recently, the primary amine-imine catalyst with an (R,R)-cyclohexane backbone was first described by our group as an efficient aminocatalyst for the aldol reaction of R-keto esters with excellent enantioselectivity.10 The primary amine-imine catalyst (Scheme 1), which is unable to be isolated due to instability,11 can be in situ generated by taking advantage of the hydrolization of a chiral diimine under acidic conditions. This could be identified obviously using ESI-MS. A catalytic amount of chiral diimine with AcOH afforded the active catalyst, which efficiently (8) (a) Xie, J. W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J. G.; Chen, Y. C. Org. Lett. 2007, 9, 413. (b) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239. (9) (a) Xu, D. Q.; Wang, Y. F.; Zhang, W.; Luo, S. P.; Zhong, A. G.; Xia, A. B.; Xu, Z. Y. Chem.;Eur. J. 2010, 16, 4177. (b) Gao, Y. J.; Ren, Q.; Wang, L.; Wang, J. Chem.;Eur. J. 2010, 16, 13068. (10) Zhu, X.; Lin, A. J.; Fang, L.; Li, W.; Zhu, C. J.; Cheng, Y. X. Chem.; Eur. J. 2011, 17, 8281. (11) For the instability of the primary amine-imine, see: (a) Xia, Q.; Ge, H.; Ye, C.; Liu, Z.; Su, K. Chem. Rev. 2005, 105, 1603. (b) Lopez, J.; Liang, S.; Bu, X. Tetrahedron Lett. 1998, 39, 4199. (c) Campbell, E. J.; Nguyen, S. T. Tetrahedron Lett. 2001, 42, 1221. (d) Sun, Y.; Tang, N. J. Mol. Catal. A: Chem. 2006, 255, 171. (e) Daly, A. M.; Dalton, C. T.; Renehan, M. F.; Gilheany, D. G. Tetrahedron Lett. 1999, 40, 3617. (f) Renehan, M. F.; Schanz, H. J.; McGarrigle, E. M.; Dalton, C. T.; Daly, A. M.; Gilheany, D. G. J. Mol. Catal. A: Chem. 2006, 231, 205. Org. Lett., Vol. 13, No. 16, 2011
In the preliminary investigation, a series of diimine precatalysts with an (R,R)-diphenylethane backbone were prepared (Figure 1, 1a 1g). When acidified with AcOH in THF, the diimines largely converted to the primary amineimine, which could be obviously detected by the ESI-MS analysis of the mixture.13 The addition of 4-hydroxycoumarin 2a to 2-cyclohexen-1-one was selected as a model reaction to explore the feasibility of the proposed strategy catalyzed by a chiral primary amine-imine catalyst. The results are summarized in Table 1. Initially, diimine 1a was investigated as the precatalyst, and the reaction failed to proceed without any additive. When added with 10 equiv of AcOH, 1a afforded the desired product in 96% yield with 86% ee in THF at room temperature (entry 1). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid, and therefore no pseudodiastereomers are observed during HPLC analysis.7 9 (R,R)-dpen as catalyst was also investigated but gave the desired adduct with a lower ee value (entry 2). Subsequently, different diimines 1b 1g were probed as precatalysts, and 1f exhibited the best result (entry 7). We then investigated the effects of solvents with catalyst 1f. The results (entries 7 and 9 12) showed that the best solvent was THF. To further improve the enantioselectivity, the effect of (12) For examples of asymmetric reactions of R,β-unsaturated ketones catalyzed by primary amines, see: (a) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403. (b) Xie, J. W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y. C.; Wu, Y.; Zhu, J.; Deng, J. G. Angew. Chem., Int. Ed. 2007, 46, 389. (c) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49. (d) Yang, Y. Q.; Zhao, G. Chem.; Eur. J. 2008, 14, 10888. (e) Liu, C.; Lu, Y. X. Org. Lett. 2010, 10, 2278. (f) Xue, F.; Liu, Lu.; Zhang, S. L.; Duan, W. H.; Wang, W. Chem.;Eur. J. 2010, 27, 7979. (g) Zhu, Q.; Lu, Y. X. Chem. Commun. 2010, 13, 2235. (13) For ESI-MS spectra, see Supporting Information: 1f was acidified with AcOH in THF. 4383
Table 1. Asymmetric Michael Addition of 4-Hydroxycoumarin to 2-Cyclohexen-1-one
entrya
catalyst
solvent
additive
t (h)
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
1a (R, R)-dpen 1b 1c 1d 1e 1f 1g 1f 1f 1f 1f 1f 1f 1f 1fd 1fe 1ff 1fg 1fh
THF THF THF THF THF THF THF THF Toluene MeOH CH2Cl2 Et2O THF THF THF THF THF THF THF THF
--/AcOH --/AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH C2H5COOH C3H7COOH hexanoic acid hexanoic acid hexanoic acid hexanoic acid hexanoic acid hexanoic acid
24 24 36 36 36 36 36 36 48 72 48 72 36 36 36 36 36 72 36 36
--/92 92/96 93 91 90 92 94 92 68 57 90 9 93 94 94 94 94 78 76 78
--/86 49/75 88 87 86 89 91 88 79 63 88 68 92 93 95 90 95 95 91 92
Table 2. Asymmetric Michael Addition of 4-Hydroxycoumarins to Cyclic Enones
a Unless otherwise noted, the reaction was carried out with 0.1 mmol of 2-cyclohexen-1-one, 0.1 mmol of 4-hydroxycoumarin, 10 equiv of a Brønsted acid, and a 10 mol % loading of diimine in 0.5 mL of THF at room temperature. b Isolated yield. c Determined by chiral HPLC. The absolute configurations were established as R. d With 5 mol % loading of 1f. e With 20 mol % loading of 1f. f Carried out at 0 °C. g With 5 equiv of hexanoic acid loading. h With 20 equiv of hexanoic acid loading.
additives was investigated. A series of Brønsted acids screened showed that aliphatic acids had a slight effect on enantioselectivity enhancement. Hexanoic acid was the best additive which afforded the adduct with 95% ee (entries 13 15). Decreasing the catalyst loading of 1f to 5 mol % led some loss of ee value while increasing the 1f loading to 20 mol % provided no improvement of enantioselectivity (entries 16 17). The reaction temperature was also studied. It seems that lowering the reaction temperature to 0 °C led to little improvement of the enantioselectivity and caused low reactivity (entry 18). In addition, the loading of hexanoic acid is probed and 10 equiv of hexanoic acid to 4-hydroxycoumarin afforded the product with the highest enantioselectivity (entries 19 20). Optimization of reaction conditions revealed that the reaction carried out with a 10 mol % loading of 1f and 10 equiv of hexanoic acid in 0.5 mL of THF at room temperature afforded the adduct with the best reactivity (94% yield) and enantioselectivity (95% ee) in 36 h (entry 15). With the optimized conditions, the substrate generality was investigated. As summarized in Table 2, generally, the Michael reactions proceeded smoothly with a variety of substituted 4-hydroxycoumarins and 2-cyclohexen-1-one to generate the corresponding adducts with high enantioselectivities. The 4-hydroxycoumarins with electron-donating 4384
a Carried out with 0.1 mmol of enone, 0.1 mmol of substituted 4-hydroxycoumarin compounds, 10 equiv of hexanoic acid, and a 10 mol % loading of diimine 1f in 0.5 mL of THF at room temperature for 36 h. b Isolated yield. c Determined by chiral HPLC. d The absolute configuration was established as R.
substituents (entries 2 6) and electron-withdrawing substituents (entries 7 9) on aromatic rings were introduced and showed good toleration in the reaction. It appears that the position and electronic properties of substituents on aromatic rings have a limited effect on the activity and selectivity of this process. Benzo-4-hydroxycoumarins were also investigated (entries 10 11). Although slightly lower yields of the Michael adducts were obtained, high enantioselectivities were maintained. 2-Cyclohepten-1-one and 2-cycloocten-1-one were employed as electrophiles in the process and showed good enantioselectivities (entries 12 13). Benzalacetone and chalcone as acyclic enones were also introduced and were well-tolerated (entries 14 15). Moreover, we probed the asymmetric Michael addition reaction of 4,4-dimethylcyclohex-2-enone, which gave the adduct in a high yield with 95% ee (entry 16). In addition, the reaction can be successfully extended utilizing 4-hydroxy-6-methyl-2-pyrone as the Michael donor, which afforded an excellent result (entry 17). 1-Methyl-4-hydroxycarbostyril, a 4-hydroxycoumarin analogue, was also employed, Org. Lett., Vol. 13, No. 16, 2011
Figure 2. Proposed transition state for the reaction and X-ray crystal structure of compound 4a.
and high enantioselectivity (88% ee) was achieved with a little reduction of yield (entry 18). The absolute configuration of product 4a was determined to be R by using single-crystal X-ray diffraction (Figure 2).14 Based on the result, we proposed a transition state for the catalytic asymmetric Michael reaction. The chiral diimine is hydrolyzed under acidic conditions and converted to a primary amine-imine catalyst. The interaction (14) CCDC 823543 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc. cam.ac.uk/ data_request/cif.
Org. Lett., Vol. 13, No. 16, 2011
between enone and amine gives the active iminium. The 4-hydroxycoumarin introduced by hydrogen bonding is much more accessible to attack the active iminium from the Re face, affording the major stereoisomer. In conclusion, we have successfully demonstrated that the in situ formed primary amine-imine catalyst is an excellent aminocatalyst for an enantioselective Michael addition reaction of substituted 4-hydroxycoumarin compounds and cyclic enones. High yields and excellent enantioselectivities were achieved for a series of substituted 4-hydroxycoumarin compounds. Cyclic enones showed excellent toleration in the process, which explored a new strategy for the synthesis of optically active polycyclic coumarin derivatives. Acknowledgment. We gratefully acknowledge the National Natural Science Foundation of China (20832001, 20972065, 21074054) and the National Basic Research Program of China (2007CB925103, 2010CB923303) for their financial support. Fundamental Research Funds for the Central Universities (1082020502) is also acknowledged. Supporting Information Available. Experimental procedures, structural proofs, NMR spectra and HPLC chromatograms of the products, and CIF file of enantiopure 4a. The material is available free of charge via the Internet at http://pubs.acs.org.
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